Mouse natural killer (NK) and natural cytotoxic (NC) cells have been shown to be closely associated with large granular lymphocytes (LGL), as has been found previously for man and rats. Procedures have been developed for highly purifying these natural effector cells, by centrifugation on Percoll density gradients and by elimination of contaminating T cells by treatment with monoclonal antibodies to Lyt 1 and 2 plus complement. Fluorescence flow cytometry studies have indicated that the mouse LGL express low amounts of Lyt 1 and no detectable Lyt 2. LGL have also been shown to account for the natural cytotoxic activity of human leukocytes against freshly harvested human tumors and it has been possible to augment such reactivity by culturing these LGL in the presence of interleukin-2. Detailed studies have been performed on the regulation of the development and reactivity of mouse NK cells. It has been shown that various biological response modifiers, including interferon, cause an in vivo increase in LGL in the spleen, along with a change in their physical characteristics. The characteristics of suppressor cells for mouse NK activity have been studied in detail and the relationship between these cells and the effector cells has been clarified. Mouse model systems for induction of hyporesponsiveness to augmentation of NK activity, after multiple inoculations of interferon, have been developed.